Biology subjects

Kao, Y.-C.

Publications and source records attributed to Kao, Y.-C..

4 recordsLinked to original sources

bioRxiv2025

Structural and biochemical basis for cannabinoid cyclase activity in marine bacterial flavoenzymes

The marine bacterial flavoenzymes Clz9 and Tcz9 can process cannabigerolic acid (CBGA) to the minor cannabinoid, cannabichromenic acid (CBCA), however, the mechanistic details of this extrinsic transformation are still obscure. Here, we report a thorough analysis of CBCA-formation by Clz9 and Tcz9 through high-resolution crystallographic characterization, biochemical analysis, and spectroscopic interrogation. Our work reveals that Clz9 and Tcz9 use different biochemical mechanisms from Cannabis cyclases and each other in their production of CBCA. Collection of a high-resolution substrate-bound structure, the first for any cannabinoid cyclase, provides key insights into how active site architecture affects substrate binding and stereoselectivity. Engineering approaches improve the stereoselectivity of CBCA formation by Clz9 and Tcz9, providing access to (R) and (S)-CBCA. Collectively, our work advances understanding of enzymatic cannabinoid formation and cements Clz9 and Tcz9 as two unique members of the BBE-like enzyme family with encouraging potential for biocatalytic cannabinoid production applications.

biochemistry↗

bioRxiv2025

Integrating 12 Spatial and Single Cell Technologies to Characterise Tumour Neighbourhoods and Cellular Interactions in three Skin Cancer Types

Cutaneous squamous cell carcinoma (cSCC), basal cell carcinoma (BCC), and melanoma - the three major skin cancers - collectively comprise over 70% of all cancer cases. Despite their prevalence, much understanding of cellular interactions in the skin cancer microenvironment is needed, both in the outer skin layer where the cancer originates and at the deeper junctional and dermal layers into which it progresses. To address this gap, we integrated 12 complementary spatial and single-cell technologies to generate orthogonally-validated cell signatures, spatial maps, and interactomes for cSCC, BCC, and melanoma. Through comprehensive comparisons and integrating these spatial methods, we provided practical benchmarking guidelines for experimental design and analysis. By identifying keratinocyte cancer cells and melanomas, we found distinct signatures of these cells compared to non-cancer keratinocytes and melanocytes. Spatial integration of transcriptomics, proteomics and glycomics uncovered cancer niches enriched for cancer initiating cells (melanocytes or keratinocytes) and fibroblast and T-cell (MKFT) clusters, with altered tyrosine and pyrimidine metabolism. Ligand-receptor analysis across >700 cell-type combinations and >1.5 million interactions highlighted key roles for CD44, integrins, and collagens, with CD44-FGF2 emerging as a potential therapeutic target. Consistently, melanoma showed strong MFT interactions, validated by Opal Polaris, RNAScope, Proximal Ligation Assay and two additional single-cell spatial platforms (making a total of 14 technologies). For population-scale generalisation, genetic associations from >500,000 individuals were mapped onto spatial skin tissues, identifying SNPs enriched in domains containing melanocytes and T cells and their ligand-receptor pairs, shedding light on functional mechanisms linking genetic heritability to cells within cancer tissue. We built an interactive multiomics resource for exploring spatially-resolved molecular signatures and cellular crosstalk in skin cancer, available at https://skincanceratlas.com.

cancer biology↗

bioRxiv2025

The search for Lake Superior ciscoes as described by W. Koelz in 1929 yields a surprising discovery: Shortnose Cisco (Coregonus reighardi), a presumed extinct species

The Laurentian Great Lakes (LGL) formed following the retreat of the Wisconsin glaciation 15-9 ka and provided a vast volume of freshwater habitat for coregonines, which included a diverse endemic complex of ciscoes. However, anthropogenic impacts in the 19th and 20th centuries resulted in declines and losses of ciscoes, leaving only Lake Superior with a relatively intact complex that still dominates its prey fish community. In the 1920s, W. Koelz described six putative cisco species from Lake Superior: Coregonus artedi, C. hoyi, C. kiyi, C. zenithicus, C. reighardi, and C. nigripinnis. Of these, artedi, hoyi and kiyi remain extant and abundant in Lake Superior, zenithicus is considered extirpated throughout the LGL except in Lake Superior, and reighardi and nigripinnis are considered extinct and had been synonymized as zenithicus in Lake Superior. Using an integration of morphological and genetic approaches, we present results reaffirming the presence of artedi, hoyi, and kiyi, and new evidence for the presence of reighardi, a species thought to be extinct. Our analysis did not elucidate the presence of zenithicus and nigripinnis, leaving their status unresolved. The principal morphological characters that discriminate artedi, hoyi, kiyi, and reighardi are related to habitat and trophic (ecological) specialization and foster niche segregation: eye size, gill raker length, and gill raker spacing, the same as those that foster niche segregation in subarctic European whitefishes. The discovery of reighardi is expected to stimulate new interest in the development of conservation and restoration plans for rare and imperiled cisco species in the LGL and other freshwater lakes throughout the Northern Hemisphere, and our integrated morphological and genetic approach can benefit these efforts by providing insights for the evolution, diversity, and ecology of ciscoes.

evolutionary biology↗

bioRxiv2023

Benchmarking robust spatial transcriptomics approaches to capture the molecular landscape and pathological architecture of archived cancer tissues

AbtractsApplying spatial transcriptomics (ST) to explore a vast amount of formalin-fixed paraffin-embedded (FFPE) archival cancer tissues has been highly challenging due to several critical technical issues. In this work, we optimised ST protocols to generate unprecedented spatial gene expression data for FFPE skin cancer. Skin is among the most challenging tissue types for ST due to its fibrous structure and a high risk of RNAse contamination. We evaluated tissues collected from ten years to two years ago, spanning a range of tissue qualities and complexity. Technical replicates and multiple patient samples were assessed. Further, we integrated gene expression profiles with pathological information, revealing a new layer of molecular information. Such integration is powerful in cancer research and clinical applications. The data allowed us to detect the spatial expression of non-coding RNAs. Together, this work provides important technical perspectives to enable the applications of ST on archived cancer tissues.

pathology↗